The Role of Endoplasmic Reticulum (ER) Stress in Development of Leptin Resistance: Obesity is an escalating problem that constitutes a major threat to global human health. The alarming increase in the incidence of obesity among the pediatric population casts the disease into a new and more concerning dimension. Although urgent therapeutic interventions are needed, effective therapeutic modalities to prevent or cure the development of obesity is limited. Leptin is an adipocyte-secreted hormone that communicates available body energy stores to the brain. Through its action on the hypothalamic neurons, leptin suppresses food intake and increases energy expenditure. Although it was discovered more than a decade ago, leptin has not evolved as a therapeutic modality for the treatment of obesity because of the existence of leptin resistance in most of the obese population. Our laboratory has recently demonstrated that obesity creates endoplasmic reticulum (ER) stress and initiates unfolded protein response (UPR) signaling in the hypothalamus. This in turn leads to inhibition of leptin receptor signaling and creation of leptin resistance in obese mice. Our proposal is based on these findings and aims to investigate the molecular mechanisms of ER-stress mediated leptin resistance in vitro through cell signaling experiments and the role of ER folding capacity in the development of leptin resistance in vivo through a genetically engineered mouse model. Public Health Relevance: Therapeutic modalities that will suppress appetite might be useful in preventing and curing obesity, which is one of the most serious public health threats. The strong appetite suppressing effect of leptin does not work in obese people due to leptin resistance. Understanding the molecular mechanisms of leptin resistance might help us discover new drugs to overcome leptin resistance and treat obesity.